The invention relates to novel pyridazino[4,5-b][1,5]oxazepinone, -thiazepinone and -diazepinone derivatives as well as to pharmaceutical compositions containing these compounds.
The compounds according to the invention have valuable biological properties, namely, they show significant memory-enhancing effect, which is associated with considerable neuroprotective character.
According to a nowadays accepted view, glutamate the most important neurotransmitter of stimulating character, plays a decisive role in the memory processes. In pathological conditions resulting in dementia, the underfunction of the glutamatergic system can be demonstrated [Danysz W. et al., Drug News and Persp., 8, 263 (1995)]. The role of ionotropic glutamate receptors of the NMDA type played in memory functions has been experimentally proved; following their special, voltage-dependent activation the calcium permeability is enhanced, whereby certain memory processes can be readily explained on the neuronal level. Accordingly, compounds having glutamate agonist effect may stimulate the cognitive functions [Granger, R. et al., Synapse, 15, 326 (1993); Nicholson, C. D. et al., Psychopharmacology, 101, 147 (1994)). The effect of aniracetame and related compounds, which are long used in the therapy as memory-enhancers, is also based on the potentiation of the glutamate neurotransmission [Ito, l. et al., J. Physiol., 424, 533 (1990)].
Overactivity of the glutamatergic system, however, can result in excitotoxicity-induced neuronal cell loss, which is observed in several neurodegenerative disorders. In such diseases glutamate agonists can counter-balance the memory deficit resulted from the neuronal damage, while neuroprotective effect can be expected from glutamate antagonists.
Now it has been found that the novel compounds according to the invention are very effective in in vivo memory models, wherein they simultaneously show NMDA-activating and AMPA-inhibiting effects. Such novel type drugs of combined effect may result in definite advantages over the known memory-enhancing agents. Namely, reduced risk of side-effects (e.g. epileptogenic or neurone-damaging effect) inherently associated with the target effects (i.e. enhancing glutamatergic neurotransmission) during long-term use can be expected. Further, the AMPA antagonist character of the compounds can result in moderation of excitotoxicity-related neurodegeneration. Thus, besides palliative treatment the compounds of the invention may also slow down the progress of the diseases.
Some derivates of formula (I) of the present invention, in which R stands for hydrogen atom, R1 is methyl group, X is oxygen or sulphur atom, W is methylene group and Y stands for a group of formula NR3, wherein R3 is hydrogen atom or benzyl group, are mentioned in the literature as intermediates in the synthesis of novel pyridazino [4,5-b][1,5]oxazepines [P. Matyus et al.: Bioorganic and Medicinal Chemistry Letters, Vol. 7, No. 22, pp. 2857-2862 (1997)], but the synthesis, the physical data and the biological activity of these compounds has not been described so far.
The invention relates to novel pyridazino[4,5-b][1,5]oxazepinone, -thiazepinone and -diazepinone derivatives of general formula (I) 
wherein
R stands for hydrogen atom or a group of formula NHR4, wherein R4 stands for hydrogen, C1-4 alkyl or C2-5 acyl group,
R1 stands for C1-4 alkyl or C2-4 alkenyl group, which may be substituted by a phenyl group, or phenyl group,
W stands for methylene or carbonyl group,
X and Y stand independently for oxygen or sulphur atom, SO, SO2 or NR3 group, wherein R3 is hydrogen atom, C1-4 alkyl group or a group of formula (II), 
xe2x80x83wherein R2 stands for hydrogen or halogen atom, C1-4 alkoxy or nitro group or a group of formula NHR4, wherein R4 has the above meaning, and Z stands for methylene or carbonyl group, further n has a value of 0, 1 or 2,
xe2x80x83with the proviso that when any of X or Y stands for oxygen or sulphur atom, SO or SO2 group or a group of formula NR3,
xe2x80x83wherein R3 stands for hydrogenatom or a C1-4 alkyl group, then the other may stand only for an NR3 group, wherein R3 stands for a group of formula (II)xe2x80x94wherein R2, Z and n have the above meaning
and their tautomers and the acid-addition salts of all these compounds. Furthermore, the invention relates to pharmaceutical compositions containing the compounds of general formula (I) as active agents.
In the general formula (I) the alkyl, acyl and alkenyl groups may have straight or branched chain, and the term xe2x80x9chalogen atomxe2x80x9d relates to chlorine or bromine atom.
The salts of the compounds of general formula (I) are pharmaceutically acceptable salts formed with inorganic and organic acids. Inorganic acids suitable for this purpose are e.g. hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid. From the organic acids to be used for this purpose formic acid, acetic acid, maleic and fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid and methanesulphonic acid are mentioned.
A preferred group of the compounds according to the invention of general formula (I) comprises compounds wherein R is hydrogen atom, R1 stands for methyl or cinnamyl group, X is oxygen or sulphur atom or a group of formula NCH3, W is methylene group and Y stands for a group of formula NR3, wherein R3 is a benzyl or a substituted benzyl group. Especially preferred are those compounds wherein X stands for sulphur atom.
The compounds of general formula (I) according to the invention can be prepared e.g. by the intramolecular cyclization of a compound of general formula (IIIa) 
wherein A is a hydroxyl group or a halogen atomxe2x80x94and, if desired, by the subsequent transformation of the substituents.
a) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR3xe2x80x94wherein R3 is a group of general formula (II), wherein R2, Z and n have the above meaningsxe2x80x94and the other stands for oxygen atom, a compound of general formula (IIIa) or (IIIb)xe2x80x94wherein A stands for hydroxyl group, and R, R1, R2, W, Z and n have the above meaningxe2x80x94is reacted with a base, e.g. sodium ethylate.
b) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR3xe2x80x94wherein R3 is a group of general formula (II), wherein R2, Z and n have the above meaningxe2x80x94and the other stands for sulphur atom, a compound of general formula (IIIa) or (IIIb), wherein A stands for halogen atom, and R, R1, R2, W, Z and n have the above meaning, is reacted with an inorganic sulphide, e.g. sodium sulphide.
c) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR3xe2x80x94wherein R3 stands for a group of general formula (II), wherein R2, Z and a have the above meaningxe2x80x94and the other stands for a group of formula NR3, wherein R3 is hydrogen atom or a C1-4 alkyl groupxe2x80x94a compound of general formula (IIIa) or (IIIb), wherein A is halogen atom, and R, R1, R2, W, and n have the above meaning, is reacted with ammonia or an aliphatic amine.
d) For preparing compounds of general formula (I)xe2x80x94wherein one of X and Y stands for a group of formula NR3, wherein R3 is a group of general formula (II)xe2x80x94wherein R2, Z and n have the above meaningxe2x80x94and the other is an SO or SO2 group, a compound of general formula (I)xe2x80x94wherein one of X and Y is a group of formula NR3, wherein R3 stands for a group of formula (II), wherein R2, Z and n have the above meaningxe2x80x94and the other is a sulphur atom, is reacted with an oxidating agent (e.g. alkali metaperiodate or hydrogen peroxide).
e) For preparing compounds of general formula (I)xe2x80x94wherein one of X or Y is a group of formula NR3, wherein R3 has a meaning different from benzyl groupxe2x80x94a compound of general formula (I), wherein R, R1 and W has the above meaning, further one of X and Y stands for a group of formula NR3 xe2x80x94wherein R3 is a benzyl groupxe2x80x94and the other is oxygen or sulphur atom or a SO, SO2 or NR3 group, wherein R3 is hydrogen atom or a C1-4 alkyl groupxe2x80x94is debenzylated in a known way, whereafter the product is reacted with an acid halide or alkyl halide corresponding to the desired group of general formula (II).
As mentioned above, the compounds of general formula (I) according to the invention have valuable biological activity, namely, they possess considerable memory-enhancing effect accompanied by valuable neuroprotective character.
The memory-enhancing effect of the compounds according to the invention was measured by counter-balancing the scopolamine-induced memory-deficit in rats, with oral doses of 50 mg/kg, in the passive avoidance test published by Cumin, R. et al. [Psychopharmacology, 78, 104 (1982)].
The results obtained are summarized as follows:
The AMPA antagonistic effect of the compounds was tested on rat Purkinje cells (Bleakman, D. et al., Neuropharmacology, 35, 1689 (1996)] in a concentration of 100 xcexcM, in a patch clamp experiment [Yamada, K. A. and Turetsky, D. M., Br. J. Pharmacol., 117, 1663 (1996)].
The AMPA antagonistic effect of the compounds was also tested on spreading depression of chick retina (Sheardown, M. J.: Brain Res., 1993, 607, 189) in a concentration of 20 xcexcM.
The NMDA receptor-mediated inward current evoked by the compounds was tested on rat hippocampal cell culture (Baughman, R. W. et al. in: Culturing Nerve Cells, 1992, pp. 227) in a concentration of 100 xcexcM in a patch clamp experiment.
It is expected that the compounds of general formula (I) according to the invention can be advantageously used for the manufacture of medicaments suitable for treating acute or chronic neurodegenerative diseases and/or different memory disorders, especially when the memory loss is associated with neurodegeneration of excitotoxic origin such as e.g. Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, further dementias of AIDS origin or of vascular origin in aged people
For therapeutical purposes the compounds according to the invention of general formula (I) are transformed to enteral or parenteral pharmaceutical preparations. For this purpose organic or inorganic carriers and fillers generally used in the pharmaceutical industry can be employed, such as water, gelatine, arabic gum, lactose, starch, magnesium stearate, talc, plant oils, polyethylene glycols etc. The pharmaceutical composition may be of solid form such as tablets, dragees, suppositories or capsules, or it can be prepared in liquid form such as solutions, suspensions or emulsions. The above-mentioned auxiliaries can be supplemented with preserving, stabilizing, emulsifying, buffering etc. additive agents, too.
For parenteral administration the active agent is formulated as a sterile solution or suspension; in such cases the sterile carrier may contain as an adjuvant e.g. a local anesthetic, a stabilizing and/or a buffering agent.
The dose to be administered to the patient depends on several factors such as the method of use, the type and severity of the disease as well as the weight and age of the patient. The daily dose may amount to 0.5-1000 mg, preferably 20-200 mg and can be administered at once or divided to several parts.
The invention also relates to a method of treating conditions associated with the acute or chronic form of neurodegenerative diseases and/or different memory disorders, especially when the memory loss is associated with neurodegeneration of excitotoxic origin such as e.g. Alzheimer""s disease, Huntington""s chorea and Parkinson""s disease, and more specifically, a method of treating mammals, which comprises the administration of the compounds of general formula (I) as the active agent.